In many diseases, for example, rheumatism, arthritis, osteoporosis, inflammatory colitis, immune deficiency syndrome, ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependent diabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer's disease, and leukemia, for example, stimulation of interleukin-1β production, an inflammatory cytokine, is observed. This interleukin-1β serves to induce synthesis of an enzyme which is considered to take part in inflammation—like collagenase and PLA2—and, when intra-articularly injected to animals, causes multiarticular damage highly resembling rheumatoid arthritis. In a healthy body, on the other hand, the activity of interleukin-1β is controlled by interleukin-1 receptor, soluble interleukin-1 receptor and interleukin-1 receptor antagonist.
From research conducted using recombinant versions of these bioactivity-inhibiting substances, anti-interleukin-1β antibodies and anti-receptor antibodies against various disease models and also from research performed using knockout mice, interleukin-1β has been found to play an important role in the body, leading to an increasing potential of substances having interleukin-1β inhibitory activity as therapeutics for such diseases.
For example, immunosuppressors and steroids, which are used for the treatment of rheumatism, have been reported to inhibit production of interleukin-1β. Among compounds currently under development, KE298, a benzoylpropionic acid compound [The Japanese Society of Inflammation (11th), 1990], for example, has been reported to exhibit inhibitory activity against interleukin-1β production although it is an immunoregulator. Inhibitory activity against interleukin-1β production is also observed on a group of compounds which are called “COX-2 selective inhibitors”, for example, nimesulide as a phenoxysulfonanilide compound (DE 2333643), T-614 as a phenoxybenzopyran compound (U.S. Pat. No. 4,954,518), and tenidap (hydroxyindole compound) as a dual inhibitor (COX-1/5-LO).
Moreover, interleukin-1β production inhibitory activity is not the primary action or effect of any of these compounds so the inhibitory activity against interleukin-1β production is less than the primary action thereof.
More recently, increased synthetic research has been conducted emphasizing inhibitory activity against interleukin-1β production. Production inhibitors can be classified into (1) a group of compounds which inhibit the transfer process of an inflammatory signal to a cell nucleus and (2) another group of compounds which inhibit the enzyme ICE that functions in the processing of a precursor of interleukin-1β. Known examples of compounds presumed to have the former action (1) include SB203580 [Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI 7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP 376288), CGP47969A (Gastroenterology, 109, 812-828, 1995), hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187-198, 1996), and triarylpyrrole derivatives (WO 9705878), while known examples of compounds presumed to have the latter action (2) include VE-13,045 which is a peptide compound (Cytokine, 8 (5), 377-386, 1996).
None of these compounds, however, exhibit sufficient inhibitory activity against interleukin-1β production.
On the other hand, it is known that 5,6-diphenyl-pyridazine compounds exhibit analgesic and anti-inflammatory action (Eur. J. Med. Chem., 14, 53-60, 1979). Further, 6-phenylpyridazinones have been reported to be useful as cardio-active compounds (U.S. Pat. No. 4,404,203). Nothing has been reported, however, with respect to inhibitory activity of these pyridazine compounds against interleukin-1β production.
The present inventors previously reported in WO 99/44995 that high inhibitory activity against interleukin-1β production was observed on phenylpyridazine compounds. Recently, certain phenylpyridazine compounds having inhibitory activity against interleukin-1β production have been reported (JP 7-69894 A, WO 98/41511, WO 99/10331, WO 99/10332, WO 99/25697, WO 00/50408). These reported compounds, however, are different in chemical structure from the compounds of the present invention.